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Drug therapy for Celiac Sprue

a celiac sprue and drug therapy technology, applied in the field of celiac sprue drug therapy, can solve the problems of no good treatment for the disease, few patients respond poorly or not at all, and erroneous diagnosis of eczema

Inactive Publication Date: 2007-09-04
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]In another aspect, the invention provides pharmaceutical formulations comprising a tTGase inhibitor and a pharmaceutically acceptable carrier. In one embodiment, the formulation also comprises one or more glutenases, as described in U.S. Provisional Application No. 60/392,782 filed Jun. 28, 2002; and U.S. Provisional Application No. 60/428,033, filed Nov. 20, 2002, both of which are incorporated herein by reference. The invention also provides methods for the administration of enteric formulations of one or more tTGase inhibitors to treat Celiac Sprue. In another aspect, the tTGase inhibitors and/or pharmaceutical formulations of the present invention are useful in treating disorders where TGases are a factor in

Problems solved by technology

Itching and burning are severe, and scratching often obscures the primary lesions with eczematization of nearby skin, leading to an erroneous diagnosis of eczema.
At the present time, there is no good therapy for the disease, except to avoid completely all foods containing gluten.
A few patients respond poorly or not at all to gluten withdrawal, either because the diagnosis is incorrect or because the disease is refractory.

Method used

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  • Drug therapy for Celiac Sprue
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  • Drug therapy for Celiac Sprue

Examples

Experimental program
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example 1

Synthesis of Dihydroxyisoxazole Containing tTGase Inhibitors

[0068]Synthesis of {(S)-1-[(3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamoyl]-2-phenyl-ethyl}-carbamic acid benzyl ester (n=0, X═NH, R1═BnO, R2═(S)—Bn, R3═Br) (49). N-Cbz-L-Phe (0.30 g, 1.0 mmol) and HOBt (0.15 g, 1.1 eq) were dissolved in 2 mL DMF. 3-Bromo-5-aminomethyl-4,5-dihydroisoazole (0.18 g, 1.0 eq), prepared following a reported procedure (Rohloff et al. (1992) Tetrahedron Lett. 33(22):3113-3116), was added to the solution cooled in an ice bath followed by EDCI (0.23 g, 1.2 eq). The ice bath was removed and the stirring was continued overnight. The solution was diluted with ethyl acetate and washed with sat. NaHCO3 solution and brine. The organic layer was dried over MgSO4 and filtered. The solvent was removed by evaporation and the residue was purified by SiO2 chromatography to give the title compound as a white solid (0.24 g, 52%).

[0069]1H NMR (CDCl3, 200 MHz): δ=7.34-7.26(m, 8H), 7.17(d, 2H, J=7.6 Hz), 6.19-6....

example 2

Synthesis of Dioxoindole Containing tTGase Inhibitors

[0111]Synthesis of 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide. 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonyl chloride (0.10 g, 0.41 mmol), prepared by the reaction of the sodium salt of 5-isatinsulfonic acid with POCl3, was dissolved in 5 mL THF. This solution was cooled in an ice bath and DIEA (0.14 mL, 2.0 eq) was added slowly, followed by n-propylamine (35 uL, 1.0 eq). Stirring was continued for 40 min and the solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4 and the solvent was removed by evaporation. The residue was purified by SiO2 chromatography to give the title compound (65 mg, 60%).

[0112]1H NMR (CD3CN, 400 MHz): δ=9.17(br, 1H), 8.02(d, 1H, J=8.0 Hz), 7.93(s, 1H), 7.13(d, 1H, J=8.0 Hz), 5.62-5.58(m, 1H), 2.85-2.80(m, 2H), 1.48-1.42(m, 2H), 0.85(t, 3H, J=7.2 Hz) MS (ESI): m / z=−267.1 [M−H]−

[0113]Synthesis of 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid be...

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Abstract

Administering an effective dose of a tTGase inhibitor to a Celiac or dermatitis herpetiformis patient reduces the toxic effects of toxic gluten oligopeptides, thereby attenuating or eliminating the damaging effects of gluten.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation in part of International Application PCT / US03 / 15343, filed May 14, 2003; and claims priority to U.S. Provisional Application No. 60 / 380,761 filed May 14, 2002; to U.S. Provisional Application No. 60 / 392,782 filed Jun. 28, 2002; and to U.S. Provisional application No. 60 / 422,933, filed Oct. 31, 2002, and to U.S. Provisional Application No. 60 / 428,033, filed Nov. 20, 2002, each of which are herein specifically incorporated by reference.[0002]This invention was made with Government support under contract 9910949 awarded by the National Science Foundation. The Government has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]In 1953, it was first recognized that ingestion of gluten, a common dietary protein present in wheat, barley and rye causes a disease called Celiac Sprue in sensitive individuals. Gluten is a complex mixture of glutamine- and proline-rich glutenin and prolamine molecules a...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K31/42C07D261/04C07D413/12
CPCA61K31/42A61K38/005C07D261/04C07D413/12A61P1/00A61P1/12A61P1/14A61P3/00A61P7/06A61P17/00A61P17/02A61P17/04A61P25/00A61P25/14A61P25/16A61P25/28A61P29/00A61P35/00A61P37/00A61P37/08A61P43/00
Inventor KHOSLA, CHAITANCHOI, KIHANG
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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